Runx2, a bone-specific transcriptional regulator, is abnormally expressed in highly metastatic prostate cancer cells. Here, we identified the functional activities of Runx2 in facilitating tumor ...growth and osteolysis. Our studies show that negligible Runx2 is found in normal prostate epithelial and non-metastatic LNCaP prostate cancer cells. In the intra-tibial metastasis model, high Runx2 levels are associated with development of large tumors, increased expression of metastasis-related genes (MMP9, MMP13, VEGF, Osteopontin) and secreted bone-resorbing factors (PTHrP, IL8) promoting osteolytic disease. Runx2 siRNA treatment of PC3 cells decreased cell migration and invasion through Matrigel in vitro, and in vivo shRunx2 expression in PC3 cells blocked their ability to survive in the bone microenvironment. Mechanisms of Runx2 function were identified in co-culture studies showing that PC3 cells promote osteoclastogenesis and inhibit osteoblast activity. The clinical significance of these findings is supported by human tissue microarray studies of prostate tumors at stages of cancer progression, in which Runx2 is expressed in both adenocarcinomas and metastatic tumors. Together these findings indicate that Runx2 is a key regulator of events associated with prostate cancer metastatic bone disease.
Directed self-assembly (DSA) of block copolymers is an emergent technique for nano-lithography, but is limited in the range of structures possible in a single fabrication step. Here we expand on ...traditional DSA chemical patterning. A blend of lamellar- and cylinder-forming block copolymers assembles on specially designed surface chemical line gratings, leading to the simultaneous formation of coexisting ordered morphologies in separate areas of the substrate. The competing energetics of polymer chain distortions and chemical mismatch with the substrate grating bias the system towards either line/space or dot array patterns, depending on the pitch and linewidth of the prepattern. This is in contrast to the typical DSA, wherein assembly of a single-component block copolymer on chemical templates generates patterns of either lines/spaces (lamellar) or hexagonal dot arrays (cylinders). In our approach, the chemical template encodes desired local spatial arrangements of coexisting design motifs, self-assembled from a single, sophisticated resist.
Integrated crop–livestock systems (ICLS) are among the main viable strategies for sustainable agricultural production. Mapping these systems is crucial for monitoring land use changes in Brazil, ...playing a significant role in promoting sustainable agricultural production. Due to the highly dynamic nature of ICLS management, mapping them is a challenging task. The main objective of this research was to develop a method for mapping ICLS using deep learning algorithms applied on Satellite Image Time Series (SITS) data cubes, which consist of Sentinel-2 (S2) and PlanetScope (PS) satellite images, as well as data fused (DF) from both sensors. This study focused on two Brazilian states with varying landscapes and field sizes. Targeting ICLS, field data were combined with S2 and PS data to build land use and land cover classification models for three sequential agricultural years (2018/2019, 2019/2020, and 2020/2021). We tested three experimental settings to assess the classification performance using S2, PS, and DF data cubes. The test classification algorithms included Random Forest (RF), Temporal Convolutional Neural Network (TempCNN), Residual Network (ResNet), and a Lightweight Temporal Attention Encoder (L-TAE), with the latter incorporating an attention-based model, fusing S2 and PS within the temporal encoders. Experimental results did not show statistically significant differences between the three data sources for both study areas. Nevertheless, the TempCNN outperformed the other classifiers with an overall accuracy above 90% and an F1-Score of 86.6% for the ICLS class. By selecting the best models, we generated annual ICLS maps, including their surrounding landscapes. This study demonstrated the potential of deep learning algorithms and SITS to successfully map dynamic agricultural systems.
Genetics of schizophrenia in the South African Xhosa Gulsuner, S; Stein, D J; Susser, E S ...
Science (American Association for the Advancement of Science),
01/2020, Letnik:
367, Številka:
6477
Journal Article
Recenzirano
Odprti dostop
Africa, the ancestral home of all modern humans, is the most informative continent for understanding the human genome and its contribution to complex disease. To better understand the genetics of ...schizophrenia, we studied the illness in the Xhosa population of South Africa, recruiting 909 cases and 917 age-, gender-, and residence-matched controls. Individuals with schizophrenia were significantly more likely than controls to harbor private, severely damaging mutations in genes that are critical to synaptic function, including neural circuitry mediated by the neurotransmitters glutamine, γ-aminobutyric acid, and dopamine. Schizophrenia is genetically highly heterogeneous, involving severe ultrarare mutations in genes that are critical to synaptic plasticity. The depth of genetic variation in Africa revealed this relationship with a moderate sample size and informed our understanding of the genetics of schizophrenia worldwide.
Ezetimibe, a cholesterol-absorption inhibitor, reduces levels of low-density lipoprotein (LDL) cholesterol when added to statin treatment. However, the effect of ezetimibe on the progression of ...atherosclerosis remains unknown.
We conducted a double-blind, randomized, 24-month trial comparing the effects of daily therapy with 80 mg of simvastatin either with placebo or with 10 mg of ezetimibe in 720 patients with familial hypercholesterolemia. Patients underwent B-mode ultrasonography to assess the intima-media thickness of the walls of the carotid and femoral arteries. The primary outcome measure was the change in the mean carotid-artery intima-media thickness, which was defined as the average of the means of the far-wall intima-media thickness of the right and left common carotid arteries, carotid bulbs, and internal carotid arteries.
The primary outcome, the mean (+/-SE) change in the carotid-artery intima-media thickness, was 0.0058+/-0.0037 mm in the simvastatin-only group and 0.0111+/-0.0038 mm in the simvastatin-plus-ezetimibe (combined-therapy) group (P=0.29). Secondary outcomes (consisting of other variables regarding the intima-media thickness of the carotid and femoral arteries) did not differ significantly between the two groups. At the end of the study, the mean (+/-SD) LDL cholesterol level was 192.7+/-60.3 mg per deciliter (4.98+/-1.56 mmol per liter) in the simvastatin group and 141.3+/-52.6 mg per deciliter (3.65+/-1.36 mmol per liter) in the combined-therapy group (a between-group difference of 16.5%, P<0.01). The differences between the two groups in reductions in levels of triglycerides and C-reactive protein were 6.6% and 25.7%, respectively, with greater reductions in the combined-therapy group (P<0.01 for both comparisons). Side-effect and safety profiles were similar in the two groups.
In patients with familial hypercholesterolemia, combined therapy with ezetimibe and simvastatin did not result in a significant difference in changes in intima-media thickness, as compared with simvastatin alone, despite decreases in levels of LDL cholesterol and C-reactive protein. (ClinicalTrials.gov number, NCT00552097 ClinicalTrials.gov.).
The association between suboptimal infant feeding practices and growth faltering is well-established. However, most of this evidence comes from cross-sectional studies. To prospectively assess the ...association between suboptimal infant feeding practices and growth faltering, we interviewed pregnant women at 28-32 weeks' gestation and followed-up their offspring at postnatal months 3, 9, 16 and 24 months in rural Bangladesh. Using maternal recall over the past 24 hours, exclusive breastfeeding (EBF) status at 3 months, age at complementary feeding (CF) initiation, and receipt of minimum acceptable diet (MAD; as defined by WHO) at 9 months were assessed. Infant length and weight measurements were used to produce length-for-age (LAZ) and weight-for-length (WLZ) z-scores at each follow-up. Generalized estimating equations were used to estimate associations of LAZ and WLZ with infant feeding practices. All models were adjusted for baseline SES, infant sex, maternal height, age, literacy and parity. Follow-up was completed by 2189, 2074, 1969 and 1885 mother-child dyads at 3, 9, 16 and 24 months, respectively. Stunting prevalence increased from 28% to 57% between infant age 3 and 24 months. EBF at 3 months and age at CF initiation were not associated with linear infant growth, but receipt of MAD at 9 months was. By age 24 months, infants receiving MAD had attained a higher LAZ compared to infants who did not receive MAD (adjusted β = 0.25, 95% CI: 0.13-0.37). Although prevalence of stunting was already high at age 3 months, ensuring infants receive a diverse, high quality diet from 6 months onwards may reduce rates of stunting in the second year of life.
Neuronal networks in the turtle spinal cord have considerable computational complexity even in the absence of connections with supraspinal structures. These networks contain central pattern ...generators (CPGs) for each of several behaviors, including three forms of scratch, two forms of swim, and one form of flexion reflex. Each behavior is activated by a specific set of cutaneous or electrical stimuli. The process of selection among behaviors within the spinal cord has multisecond memories of specific motor patterns. Some spinal cord interneurons are partially shared among several CPGs, whereas other interneurons are active during only one type of behavior. Partial sharing is a proposed mechanism that contributes to the ability of the spinal cord to generate motor pattern blends with characteristics of multiple behaviors. Variations of motor patterns, termed deletions, assist in characterization of the organization of the pattern-generating components of CPGs. Single-neuron recordings during both normal and deletion motor patterns provide support for a CPG organizational structure with unit burst generators (UBGs) whose members serve a direction of a specific degree of freedom of the hindlimb, e.g., the hip-flexor UBG, the hip-extensor UBG, the knee-flexor UBG, the knee-extensor UBG, etc. The classic half-center hypothesis that includes all the hindlimb flexors in a single flexor half-center and all the hindlimb extensors in a single extensor half-center lacks the organizational complexity to account for the motor patterns produced by turtle spinal CPGs. Thus the turtle spinal cord is a valuable model system for studies of mechanisms responsible for selection and generation of motor behaviors. NEW & NOTEWORTHY The concept of the central pattern generator (CPG) is a major tenet in motor neuroethology that has influenced the design and interpretations of experiments for over a half century. This review concentrates on the turtle spinal cord and describes studies from the 1970s to the present responsible for key developments in understanding the CPG mechanisms responsible for the selection and production of coordinated motor patterns during turtle hindlimb motor behaviors.
Childhood emotional maltreatment (CEM) increases the likelihood of developing an anxiety disorder in adulthood, but the neural processes underlying conferment of this risk have not been established. ...Here, we test the potential for neuroimaging the adult brain to inform understanding of the mechanism linking CEM to adult anxiety symptoms.
One hundred eighty-two adults (148 females, 34 males) with a normal-to-clinical range of anxiety symptoms underwent structural and functional magnetic resonance imaging while completing an emotion-processing paradigm with facial expressions of fear, anger, and happiness. Participants completed self-report measures of CEM and current anxiety symptoms. Voxelwise mediation analyses on gray-matter volumes and activation to each emotion condition were used to identify candidate brain mechanisms relating CEM to anxiety in adulthood.
During processing of fear and anger faces, greater amygdala and less right dorsolateral prefrontal (dlPFC) activation partially mediated the positive relationship between CEM and anxiety symptoms. Greater right posterior insula activation to fear also partially mediated this relationship, as did greater ventral anterior cingulate (ACC) and less dorsal ACC activation to anger. Responses to happy faces in these regions did not mediate the CEM-anxiety relationship. Smaller right dlPFC gray-matter volumes also partially mediated the CEM-anxiety relationship.
Activation patterns of the adult brain demonstrate the potential to inform mechanistic accounts of the CEM conferment of anxiety symptoms. Results support the hypothesis that exaggerated limbic activation to negative valence facial emotions links CEM to anxiety symptoms, which may be consequent to a breakdown of cortical regulatory processes.
South Africa's history and current social conditions suggest that mental disorders are likely to be a major contributor to disease burden, but there has been no national study using standardized ...assessment tools.
The South African Stress and Health Study was a nationally representative in-person psychiatric epidemiological survey of 4351 adults (aged 18 years) that was conducted as part of the WHO World Mental Health (WMH) Survey Initiative between January 2002 and June 2004. Twelve-month prevalence and severity of DSM-IV disorders, treatment, and sociodemographic correlates were assessed with Version 3.0 of the WHO Composite International Diagnostic Interview (CIDI 3.0).
The 12-month prevalence of any DSM-IV/CIDI disorder was 16.5%, with 26.2% of respondents with disorder classified as severe cases and an additional 31.1% as moderately severe cases. The most common disorders were agoraphobia (4.8%), major depressive disorder (4.9%) and alcohol abuse or dependence (4.5%). Twenty-eight percent of adults with a severe or moderately severe disorder received treatment compared to 24.4% of mild cases. Some 13.8% of persons with no disorder received treatment. Treatment was mostly provided by the general medical sector with few people receiving treatment from mental health providers.
Psychiatric disorders are much higher in South Africa than in Nigeria and there is a high level of unmet need among persons with severe and moderately severe disorders.
We present an overview of Runx involvement in regulatory mechanisms that are requisite for fidelity of bone cell growth and differentiation, as well as for skeletal homeostasis and the structural and ...functional integrity of skeletal tissue. Runx-mediated control is addressed from the perspective of support for biological parameters of skeletal gene expression. We review recent findings that are consistent with an active role for Runx proteins as scaffolds for integration, organization and combinatorial assembly of nucleic acids and regulatory factors within the three-dimensional context of nuclear architecture.
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